Further studies on dimethylnitrosamine metabolism, activation and its ability to cause liver injury.
Effects were studied of aminoacetonitrile (AAN), dibenamine (DB) diethyldithiocarbamate (DDTC) dimethylformamide (DMF), disulfiram (DS), and 2-mercapto-1-methylimidazole (MMI) on the in vitro dimethylnitrosamine (DMN) metabolism to CO2, covalent binding (CB) of DMN metabolites to nucleic acids in liver slices, DMN demethylase (DMNase) in male rat liver microsomes or 9,000 g supernatants and CB to microsome of 9,000 g supernatant proteins. Effects of those chemicals on DMN-induced rat liver necrosis were also studied, except for DS whose preventive effect was previously reported by our laboratory. All the chemicals significantly prevented DMN-induced liver necrosis, except for MMI that had no effect. All these compounds when added to incubation mixtures containing liver slices from Sprague-Dawley rats, significantly inhibited transformation of DMN to CO2 and CB to nucleic acids and when they were injected into animals and liver slices prepared afterwards, they did so except for MMI and DMF that had no effect. None of the chemicals tested except DDTC and MMI modified CB to microsome proteins whereas the CB to 9,000 g supernatant proteins was significantly decreased by all the chemicals except MMI. DMNase activity either in microsomes or 9,000 g supernatants was significantly inhibited by all the compounds except MMI.
D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005557:Formaldehyde / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009696:Nucleic Acids / Q000378:metabolism; D051381:Rats
D009696:Nucleic Acids; D002245:Carbon Dioxide; D005557:Formaldehyde; D004128:Dimethylnitrosamine